Ingestion of many naturally-occurring compounds, as well as many synthetic drugs, produces "phototoxicity" in humans and animals, so that subsequent exposure to light causes skin or vision damage, or induction or acceleration of cancer. To synthetically modify these drugs to avoid this side effect is a difficult task because of uncertainty about the molecular and mechanistic basis for this undesired photobiological activity, so there have been very few suggestions of possible approaches which might be successful in overcoming this inherent tendency towards phototoxicity in a drug. This proposal describes three mechanistically-derived approaches to the rational synthesis of new chemotherapeutic agents of dramatically lessened phototoxicity. These approaches will be tested in the synthesis of new compounds expected to exhibit high antimalarial activity, yet be non-phototoxic. Success with these compounds will not only result in new antimalarial compounds which are desperately needed,but will also demonstrate the validity of a mechanistically-derived approach to solving the problem of phototoxicity in other dissimilar classes of compounds which also suffer from this side effect.